During the previous grant period we developed an in vivo retinal gene delivery/expression system involving recombinant AAV that is efficient, cell type specific and persistent. This approach leads to prolonged (>8 month) survival of photoreceptor cells in an animal model of autosomal dominant Retinitis Pigmentosa (RP) when a therapeutic ribozyme gene is included. Using this system to deliver the neurotrophin CNTF, we found rescue of RP-like retinal dystrophies in several animal models, including P23H and S334ter rod opsin transgenic (Tg) rats and the P216L rds/peripherin TG mouse. We propose to extend this evaluation of therapeutic cytokines by additionally studying a related cytokine LIF and the CNTF high affinity receptor CNTFRa in a more diverse range of retinal dystrophy animal models. We will test each gene in animal models using AAV vectors containing promoters we developed for exclusive expression in rods, cones or RPE cells. Animal models include two that are genetically based but affect different photoreceptor specific genes (P23H rod opsin Tg rat and P216L Tg mouse), one that is immune system mediated (experimental cancer-associated retinopathy, CAR, in the rat) and one in which rod outer segments never form and cones degenerate reproducibly over a 2-3 month period after birth (rho -/- knockout mouse). When efficacy is proven in rodents, that therapy will be scaled up and tested in P347S Tg pigs. These experiments test three ideas: 1) either or both components of trophic factor/receptor systems may need to be up-regulated in the same of different retinal cells to optimally effect retinal rescue, 2) retinal rescue using cytokine/receptor gene delivery may be independent of the proximal cause of the retinopathy and 3) cones as well as rods might be preserved if the therapeutic gene is appropriately delivered and expressed. Our ultimate aim is to gain a sufficient understanding of how this class of potentially generally therapeutic genes should be expressed in the retina to most effectively delay a variety of retinopathies without toxicity. This will allow us to focus rationally on one therapeutic approach with broad utility for retinal degenerations.